# Metabolic pathways within cTfh subsets and glucose-dependent activation of cTfh17 in SLE and healthy individuals

## TL;DR

This study explores how glucose metabolism affects specific T cell subsets in lupus patients and healthy individuals, revealing that glycolysis is crucial for cTfh17 cell activity.

## Contribution

The study identifies distinct metabolic dependencies among cTfh subsets and highlights glycolysis as a key factor in cTfh17-mediated B cell activation in SLE.

## Key findings

- cTfh17 cells from SLE patients and healthy controls show higher glycolytic activity than cTfh1 and cTfh2.
- Glucose deprivation reduces costimulatory molecule expression and cytokine production in cTfh17 cells.
- Glycolysis inhibition decreases B cell activation capacity of cTfh17 cells, especially in SLE patients.

## Abstract

Cellular metabolism plays a key role in T cell biology. Increased glycolysis and mitochondrial respiration have been identified in CD4+ helper T cells from both patients with systemic lupus erythematosus (SLE) and lupus mouse models. Inhibiting this metabolic activity can reduce T cell activation and ameliorate disease symptoms in lupus mice. However, the metabolic differences among circulating follicular helper T (cTfh) cell subsets in patients with SLE versus healthy controls (HCs) have not been thoroughly studied. While the frequencies of cTfh cells and their subsets were similar between patients with SLE and HCs, patients exhibited a higher proportion of activated ICOS+ programmed cell death 1–positive cells, which correlated with disease activity. cTfh17 cells from both patients with SLE and HCs demonstrated heightened glycolytic activity and expression of glycolysis-related genes compared with cTfh1 and cTfh2. Glucose deprivation significantly diminished costimulatory molecule expression and cytokine production, including IL-17A, IL-10, IL-2, and TNF-α. Glycolysis inhibition reduced the B cell activation capacity of cTfh17 cells. This glucose dependence was more pronounced in cTfh17 than cTfh2 from patients with SLE, but it similarly affected both cTfh2 and cTfh17 cells from HCs. These findings highlight distinct metabolic dependencies among cTfh subsets and the critical role of glycolysis in cTfh17-mediated B cell activation in SLE.

Glucose metabolism is particularly important for cTfh17 activity and may be a therapeutic target for SLE.